The Role of 4-IBB in T Cell and APC Interactions

描述（由申请人提供）：这是一份修订后的申请，用于继续研究TNFR家族共刺激成员对T细胞应答的调节。我们将继续努力研究4-1BB（CD 137）在驱动CD 4和CD 8记忆的产生和持久性中的作用和功能。这些研究背后的假设是，4-1BB信号促进T细胞的克隆扩增和积累，部分通过调节T细胞增殖，部分通过抑制凋亡。我们将使用几种体内系统研究4-1BB的功能，当4-1BBL被阻断时，以及当4 -1BB不存在时，使用来自与4-1BB-/-小鼠杂交的转基因小鼠的T细胞追踪OT-I CD 8和OT-II CD 4转基因T细胞。我们将研究4-1BB信号在不同炎症条件下对记忆产生和寿命的贡献，包括1型和2型细胞因子反应。此外，我们将展示4-1BB/4-1BBL相互作用是如何受到青睐的，以及CD 4细胞、CD 8细胞或非T细胞是否存在差异使用。最后，将次级淋巴器官中的记忆与肺部炎症相关的外周记忆反应进行比较。 T细胞共刺激正成为一个越来越复杂的课题，越来越多的分子被定义为可以正向调节T细胞。我们认为，这种过多的分子最终将在几个方面得到解释。一种是定量模型，即几种分子将同时执行相同的功能，但每种分子对T细胞都是绝对必要的。另一种是动力学模型，在这种模型中，几个分子将以时间的方式一个接一个地工作，在响应T细胞寿命的不同时间。最后，随着抗原反应性T细胞分化并变得长寿，它们对共刺激分子的需求和/或使用将改变。这个应用程序将有助于描述TNFR家族的一个成员在产生和维持T细胞记忆中的作用。我们相信，这些研究将提供一个框架的共刺激模型，包括多个受体/配体相互作用。此外，它将有助于定义如何根据T细胞的类型和T细胞的生命阶段有效地靶向T细胞应答以用于疫苗接种或治疗目的。

DESCRIPTION (provided by applicant): This is a revised application for continuation of a grant to study regulation of T cell responses by costimulatory members of the TNFR family. Our continued efforts will examine the role and function of 4-1BB (CD137) in driving the generation and persistence of CD4 and CD8 memory. The hypothesis behind these studies is that 4-1BB signals promote clonal expansion and accumulation of T cells, in part by regulating T cell proliferation and in part by suppressing apoptosis. We will investigate the function of 4-1BB using several in-vivo systems, tracking OT-I CD8 and OT-II CD4 transgenic T cells when 4-1BBL is blocked, and when 4-1BB is absent, using T cells from transgenic mice crossed to 4-1BB-/- mice. We will investigate the contribution of 4-1BB signals to memory generation and longevity under conditions of varying inflammation, including Type 1 and Type 2 cytokine responses. In addition, we will show how 4-1BB/4-1BBL interactions are favored and whether there is differential use by CD4 cells, CD8 cells, or non-T cells. Lastly, memory in secondary lymphoid organs will be compared to peripheral memory responses associated with lung inflammation. T cell costimulation is becoming an ever increasingly complicated subject with more and more molecules being defined that may positively regulate a T cell. We think this plethora of molecules will ultimately be explained in several ways. One is a quantitative model, in that several molecules will perform the same function at the same time, but with each being absolutely essential to the T cell. Another is a kinetic model, where several molecules will work in a temporal fashion, one after the other, at different times in the lifespan of a responding T cell. Lastly, as antigen-reacting T cells differentiate and become long-lived, their requirements and/or usage of costimulatory molecules will change. This application will aid in delineating the role of one member of the TNFR family in generating and maintaining T cell memory over time. We believe these studies will provide a framework for a model of costimulation that incorporates multiple receptor/ligand interactions. Moreover, it will aid in defining how T cell responses can be effectively targeted for vaccination or therapeutic purposes depending on the type of T cell and the stage in the life of the T cell.